The P.I. has been investigating hypotheses regarding the role of one's sex in understanding schizophrenia (SCZ) for 20 years. This first resubmission, a competing continuation of MH56956 on sex differences in brain abnormalities in SCZ (ongoing since 1997), proposes to investigate potential mechanisms to explain sex differences in the brain in SCZ. Studies, including our own, have shown that high levels of maternal cytokines (IL-8 and TNF-a) during late fetal development (same time period as sexual differentiation of the brain), significantly increased the risk for SCZ, other psychoses and brain abnormalities associated with these disorders. Receptors for these cytokines have been located in hippocampus (HIPP), hypothalamus (HYPTH), amygdala (AMYG), and locus coeruleus, stress response circuitry involved in the hypothalamic- pituitary-adrenal (HPA) system and affective regulation, regions also found to be sexually dimorphic. Thus, we will test whether abnormalities in the maternal-fetal cytokine environment predict adult affective dysregulation and HPA dysfunction in SCZ and affective psychoses, with females being particularly affected. In MH56956 in which subjects are from a community sample followed from pregnancy through adulthood (New England Collaborative Perinatal Project), we identified 111 subjects with psychoses (63 nonaffective psychoses;48 affective psychoses) matched to two normal controls per case. Using stored serum from their pregnant mothers (ascertained in the mid 1960's), we will assay cytokines IL-8 and TNF-a and relate to onset of psychoses and structural brain abnormalities in HIPP, HYPTH, AMYG and cortical regions implicated in the stress response circuitry, i.e. orbitofrental cortex and anterior cingulate gyrus (MRI data already collected in the current MH56956). 30 DSM-IV SCZ, 30 bipolar psychoses and 30 comparable normal controls, equally divided by sex, will be re-recruited and undergo functional MRI (fMRI) stimuli of aversive affective arousal and blood acquisition for neuroendocrine assessments to test our hypotheses relating an abnormal maternal-fetal cytokine environment with adult functional brain activity deficits in the stress response circuitry and HPA dysfunction. There are no studies that relate a fetal exposure to explaining adult sex differences in affective and HPA dysfunctions in SCZ, a clinical problem of high impact, with the potential for development of sex-specific anti-inflammatory interventions for prevention.